The retroviruses we study were isolated from wild mice and cause a non-inflammatory neurodegenerative disease in mice similar to that caused by the unconventional agents such as scrapie. We are using this animal model to study the pathogenesis of retrovirus-induced neurodegeneration. Viral sequences: We previously showed that viral sequences within the 5' leader sequence of the viral genome influence the level of CNS infection and, if the virus contains an env gene from a neurovirulent retrovirus, the length of the incubation period of neurodegenerative disease. This sequence appears to influence the kinetics of virus replication in peripheral organs. We speculated that the effect of this sequence on CNS infection involved the fact that the CNS is susceptible to infection only until the 12th postnatal day, after which it becomes resistant. Strong support for this hypothesis has come from embryo inoculation experiments. Neonatal inoculation of the slowly replicating virus, 15-1, results in a low level CNS infection and very long incubation period of more than 6mo. However, embryo inoculation on E9 resulted in high level CNS infection and rapid disease being seen within 3 weeks postnatally. Thus, it appeared that the only constraint to CNS infection by this virus was the rate of virus replication, giving the virus a "head-start" overcame this constraint. Host Factors: We have found that whereas virus infection of the central nervous system is necessary, it is not sufficient for the expression of neurodegeneration. A postnatal developmental event(s) is required for the induction of spongiform degeneration. This event appears to occur 8-10 days postnatally. Currently the nature of this developmental event is uncertain. Mechanism of neuronal cytopathology: The role of the glial infection in this disease has been tested in vivo through selective infection of glial cells within susceptible regions of the CNS. No evidence of neuronal cytopathology was observed suggesting that glial infection alone is not sufficient for the induction of this neuronal cytopathology. A temporal study of the evolution of spongiform lesions has revealed that lesions appear in all affected areas of the CNS simultaneously within a narrow window of time ca. 10 days postnatally. Furthermore, there is a close temporal relationship between the first appearance of vacuolar neuronal degeneration and the expression of viral protein by premigration cerebellar granule neurons, suggesting that infection of the cerebellar cortex may play a central role in disease pathogenesis. These studies are providing further insight into the mechanisms by which retroviruses damage neurons and are beginning to reveal the ways in which retroviruses can adversely affect the developing brain.